Therapeutic derivatives of diphosphonates

Novel chemotherapeutic agents having utility in treating infectious diseases such as periodontal disease, certain urinary tract infections, infectious urinary tract stones, and bone cancer, are obtained by combining chemically a diphosphonate compound with a therapeutic agent effective against the foregoing diseases.

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Claims

1. A method for preparing a compound of the formula A--(V).sub.m --(R).sub.n --Z, wherein A is the residue of a pharmaceutically active antibiotic chemical entity, V is O, S, NR', CONR', CO--O, O--CO, O--CO--O, CO--S, S--CO, S--CO--S, NR'--CO, OCO--NR', NR'--CO--O, NR'--CO--NR", CO--NR", CO--NR'--NR", NR'--NR"--CO, NR'--C(.dbd.NH)--NR" or NR'--C(.dbd.NH)--NH--C(.dbd.NH)--NR" wherein R, R' and R" are H or an organic or heteroorganic group, and m and n are each 1, or one of m and n is 0,

comprising reacting a pharmaceutically active antibiotic entity of the formula A--V' wherein V' is halogen, OH, SH, NR'R", COOR', CO--X wherein X is halogen or azido, O--CO--X wherein X is halogen, O--CO--OR', CO--SR', S--CO--X, NR'--CO--X, NR'--NHR", NR'--CN, NR'--C(.dbd.NH)--NH--CN, or metal (covalently bound or ionic),
with a diphosphonate compound of the formula V'--R--Z wherein V' and R have the previous meanings and Z is ##STR10## which optionally may be protected, the composition of V' in the pharmaceutically active chemical entity of formula A--V' and in the diphosphonate compound of formula V'--R--Z being different and being selected to permit a condensation reaction therebetween.

2. A method for preparing a compound of claim 1 of the formula A--Z, comprising subjecting a compound of formula A--V', wherein A and Z have the same meaning as in claim 1, and V' is COOH, to conditions effective to convert the COOH group to Z.

3. A method according to claim 1 wherein V is NH, said compound being formed from a pharmaceutically active chemical entity wherein V' is halogen, amino, or a sulfonate ester, and a diphosphonate compound wherein V' is amino or halogen.

4. A method according to claim 1 wherein V is a tertiary amino-containing group, said compound being formed from a pharmaceutically active chemical entity wherein V' is halogen, a sulfonate ester or a secondary amino-containing group, and a diphosphonate compound wherein V' is a secondary amino-containing group or halogen.

5. A method according to claim 1 wherein V is CONR', said compound being formed from a pharmaceutically active chemical entity wherein V' is carboxyl, and a diphosphonate compound wherein V' is primary or secondary amino.

6. A method according to claim 1 wherein V is NR'CO, said compound being formed from a pharmaceutically active chemical entity wherein V' is primary or secondary amino, and a diphosphonate compound wherein V' is carboxyl.

7. A method according to claim 1 wherein V is CO--O, said compound being formed from a pharmaceutically active chemical entity wherein V' is carboxyl or a reactive carboxyl group derivative, and a diphosphonate compound wherein V' is halogen or hydroxyl.

8. A method according to claim 1 wherein V is O--CO, said compound being formed from a pharmaceutically active chemical entity wherein V' is halogen or hydroxyl, and a diphosphonate compound wherein V' is carboxyl.

9. A compound of the formula A--(V).sub.m --(R).sub.n --Z, wherein A, V, R, and Z have the same meaning as in claim 1, and m and n are independently 0 or 1.

11. A composition comprising a pharmaceutically effective amount of a compound of claim 9 and a pharmaceutically acceptable carrier.

12. A method of treating diseases selected from the group consisting of osteomyelitis, periodontal disease, urinary tract infections, infectious urinary tract stones, and bone cancer, comprising administering a compound of claim 9 in an amount effective to treat said disease.

13. A compound of claim 9 wherein A is the residue of a pharmaceutically active antibiotic compound selected fron the group consisting of an aminoglycoside, an amphenicol, an ansamycin, a.beta.-lactam, a diaminopyrimidine, a lincosamide, a macrolide, a monobactam, a nitrofuran, an oxacephem, a polypeptide, a quinolone, a quinolone analog, a sulfonamide, a sulfone and a tetracycline.

14. A compound of claim 9 wherein V is O, S, NR', CONR', CO--O, O--CO, O--CO--O, CO--S, S--CO, S--CO--S, NR'--CO, OCO--NR', NR'--CO--O, NR'--CO--NR", CO--NR'--NR", NR'--NR"--CO, NR'--C(.dbd.NH)--NR" or NR'--C(.dbd.NH)--NH--C(.dbd.NH)--NR".

15. A compound according to claim 14 wherein V is NR', CONR', OCO--NR', NR'--CO--NR", CO--NR'--NR", NR--C(.dbd.NH)--NR" or NR'--C(.dbd.NH)--NH--C(.dbd.NH)--NR".

16. A compound according to claim 14 wherein V is CO--O, O--CO, O--CO--O, S--CO, NR'--CO, NR'--CO--O, or NR'--NR"--CO.

17. A compound according to claim 14 wherein V is O, S, CO--S or S--CO--S.

19. A compound of claim 13 wherein the.beta.-lactam is selected from the group consisting of carbapenems, cephalosporins, cephamycins, and penicillins.

20. A compound of claim 9 wherein in any individual compound only one of the following conditions exist:

(a) both m and n are 0,
(b) both m and n are 1, or
(c) one of m and n is 1 and the other is 0.

Referenced Cited

U.S. Patent Documents

4621077 November 4, 1986 Rosini et al.
4746654 May 24, 1988 Breliere et al.
4820698 April 11, 1989 Degenhardt
4922007 May 1, 1990 Kieczykowski et al.
4939284 July 3, 1990 Degenhardt
5220021 June 15, 1993 Dunn et al.
5270365 December 14, 1993 Gertz et al.
5284841 February 8, 1994 Chu et al.
5374721 December 20, 1994 Schoen et al.
5524544 June 11, 1996 O'Meara et al.

Other references

  • The Merck Index, Ninth Edition, (Jan. 1976) pp. 919, 1174.

Patent History

Patent number: 5854227
Type: Grant
Filed: Jun 7, 1995
Date of Patent: Dec 29, 1998
Inventors: John F. Hartmann (Princeton Junction, NJ), Dan Farcasiu (Pittsburgh, PA)
Primary Examiner: Matthew V. Grumbling
Attorney: Donald J. Perrella
Application Number: 8/473,787